Method for the preparation of cis-4-aminotetrahydrofuran-2-carboxylates

Description

[0001] The present invention relates to a new process for the preparation of cis-4-aminotetrahydrofuran-2-carboxylic acid esters of general formula (I) and their salts.

[0002] Cis-4-Aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride (CAS 1304126-28-0) of general formula (I) (with R 1< =Me) is an important building block for the synthesis of plant protection products (WO 2012 / 130798, WO 2021 / 170464).

[0003] The first published synthesis route is by Walker et al. (Synthesis 2011, 7, 1113-1119). It involves 4-( tert- Butoxycarbonylamino)furan-2-carboxylic acid methyl ester (CAS 1170719-58-0, Wolter et al., Org. Lett. 2009, 11, 2804) is used as a precursor. 4-( tertHowever, the large-scale production of 4-butoxycarbonylamino)furan-2-carboxylic acid methyl ester is not economically viable due to the high cost of the reagents, low yields, safety risks, and phosphate waste. For example, lithiation with sec-butyllithium (34% yield) and a Curtius rearrangement with DPPA (diphenylphosphonazide) are required. Therefore, this route for the industrial-scale production of cis-4-aminotetrahydrofuran-2-carboxylic acid esters is not feasible.

[0004] Synthesis via 4-bromofuran-2-carboxylic acid methyl ester (CAS 58235-80-6, WO 2021 / 170464) is also costly due to bromination and the subsequent inefficient coupling with tert-butyl carbamate (25% yield, WO 2021 / 170464) and leads to large amounts of waste.

[0005] Therefore, there is a high demand for new, cost-effective and environmentally friendly processes for the synthesis of cis-4-aminotetrahydrofuran-2-carboxylic acid esters, which would then enable the production of the corresponding pesticides on an industrial scale.

[0006] WO 2012 / 137982 describes the reductive amination of 4-oxotetrahydrofuran-3-carboxylic acid methyl ester with benzylamine. In this substitution pattern, it is possible to first dehydrate the ketone with the benzylamine to form an enamine, which is stabilized via conjugation to the ester. The subsequent reduction of the double bond was then carried out with sodium triacetoxyborohydride.

[0007] This invention describes a new process for the preparation of cis-4-aminotetrahydrofuran-2-carboxylic acid esters starting from 4-oxotetrahydrofuran-2-carboxylic acid esters of general formula (II). The preparation of this starting material is described, for example, in WO 2016 / 205633.

[0008] In light of the prior art described above, the present invention aims to provide a cost-effective and industrially viable method for producing the aforementioned compounds. It is also desirable to obtain these compounds in high yield and high purity, thus avoiding the need for further complex purification.

[0009] The previously described problem - simple, cost-effective and large-scale production - is solved by a process for producing compounds of the general formula (I) or their salts. wherein R 1< stands for (C 1 -C 6 )alkyl or (C 3 -C 6 )cycloalkyl, characterized by the fact that in a first step compounds of the general formula (II) wherein R 1< as defined above with an amine of general formula (III) or its salts wherein R2< represents H, (C1-C4)alkyl, unsubstituted or substituted phenyl, R3< represents H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, in the presence of H 2 and a catalyst in a solvent selected from R'OH, R'OH / toluene, 2-PrOH, 2-BuOH or t-amyl alcohol, wherein R 1 as defined above, react to form compounds of the general formula (IV) or their salts where R 1 , R 2 and R 3 as defined above, and these subsequently in the presence of H 2 and a catalyst in a solvent selected from R'OH, R'OH / toluene, 2-PrOH, 2-BuOH or t-amyl alcohol, wherein R 1 as defined above, are converted to compounds of the general formula (I) or their salts.

[0010] Preferred Residue definitions for the compounds of the general formulas (I), (II), (III) and (IV) or whose salts are the following: R 1< stands for (C 1 -C 6 )Alkyl, R 2< stands for H, Phenyl, Methyl, R 3< stands for H, F in para position of the phenyl ring, Methyl-O- in para position of the phenyl ring, Methyl in ortho position of the phenyl ring.

[0011] Particularly preferred Residue definitions for the compounds of the general formulas (I), (II), (III) and (IV) or whose salts are the following: R 1< stands for CH 3 , R 2< stands for H, R 3< stands for H or Methyl in ortho position of the phenyl ring.

[0012] The reaction sequence for the production of compounds of the formula (I) or their salts are shown in Scheme 1.

[0013] The connections of the general formula (II) In the first reaction step, they react with compounds of the general formula (III) or their salts (possibly also mixtures of the compounds of the general formula (III) and their salts) hydrogen and a catalyst in a solvent to compounds of the general formula (IV) or their salts.

[0014] The amines obtained in this process can be further converted to salts of cis-4-aminotetrahydrofuran-2-carboxylic acid esters of the general formula (I) or react their salts using a catalyst and hydrogen in a solvent.

[0015] Both steps can also be combined in a single-stage process using a catalyst or a mixture of catalysts and hydrogen. Step 1:

[0016] The connections of the general formulas (III) and (IV) They can exist as free amines or in the form of their salts when acids are used; the salt form is preferred. Preferred The following acids react to form salts with compounds of the general formula (II) and / or used as additives: HCl, H2SO4, MsOH, TfOH, TFA. Especially preferred is HCl.

[0017] The pressure during the reaction ranges from 1 to 100 bar. preferred 1 to 50 bar, especially preferred 20 to 50 bar.

[0018] The temperature during the reaction ranges from 0°C to 100°C. preferred 4°C to 80°C, especially preferred 20 to 40°C.

[0019] Raney nickel, Raney cobalt, Pt / C and Pt / Alox can be used as catalysts. preferred Raney nickel and Pt / C, especially preferred Pt / C.

[0020] The catalysts are added in an amount of 0.1-10 wt% in relation to the compounds of the general formula (II) used preferred Between 0.5 and 5 wt% of the catalysts are used. The amount of catalyst used is calculated based on the dry mass of the catalysts. The catalysts can be used dry or moistened.

[0021] Additional Lewis acids can be added to the reaction mixture, such as: ZnCl₂, LiCl, MgCl₂, CeCl₃, CoCl₂, AlCl₃, FeCl₃, CaCl₂, Ti(iOPr)₄, B(OMe)₃. preferred The reaction can be carried out without a Lewis acid additive.

[0022] Suitable solvents and solvent mixtures are, for example: R 1< OH, R 1< OH / Toluene, 2-PrOH, 2-BuOH, t-Amyl alcohol; R 1< OH and R 1< OH / Toluene are preferred.

[0023] The molar ratio of the compounds of the general formula (II) and (III) is in the range of approximately 0.5 to 2, preferred 0.9 to 1.1, especially preferred 1.

[0024] If the compounds of general formula (I) occur in the form of their salts, e.g. as hydrochloride, the salt-free form can be obtained by treating the salt with a base, e.g. triethylamine. Step 2:

[0025] The connections of the general formulas (I) and (IV) They can exist as free amines or in the form of their salts with acids; the salt form is preferred. Preferred The following acids are used for salt formation with compounds of formula (II) and / or as additives: HCl, H 2 SO 4 , MsOH, TfOH, TFA. Especially preferred is HCl.

[0026] The pressure during the reaction ranges from 1 to 100 bar. preferred 1 to 20 bar, especially preferred 1 to 5 bar.

[0027] The temperature during the reaction ranges from 0°C to 100°C. preferred 20°C to 80°C, especially preferred 40 to 80°C.

[0028] Pd / C and Pd / Alox can be used as catalysts; preferred: Pd / C.

[0029] The catalysts are added in amounts of 0.1-10 wt% of the compounds of the formula (II) The amount of catalyst used is preferably 0.1–2 wt%. The amount of catalyst used is calculated based on the dry mass of the catalyst. The catalysts can be used dry or moist. Moist catalysts can be washed under an inert gas atmosphere before reaction with dry solvent to remove any adhering water. Alternatively, the water can be removed by azeotropic distillation with a suitable solvent. Toluene, for example, can be used for azeotropic distillation.

[0030] The catalyst can be reused once or, preferably, multiple times. Reactivation of the catalyst, for example by suitable washing, can be advantageous for its reuse, such as washing with methanol or acid methanol. Suitable solvents and solvent mixtures are, for example: R1 < OH, R1 < OH / toluene; preferably MeOH and MeOH / toluene.

[0031] Do the connections of the general formula fall (I) In the form of its salts, e.g. as hydrochloride, the salt-free form can be obtained by treating the salt with a base, e.g. triethylamine.

[0032] Surprisingly, it has now been found that 4-oxotetrahydrofuran-2-carboxylic acid esters with optionally substituted phenylmethylamines of the general formula (III) or their salts in high concentrations cis-Selectivity and high yield using hydrogen and a catalyst in a solvent in a reductive amination to give the corresponding N-substituted cis-4-aminotetrahydrofuran-2-carboxylic esters of the general formula (IV) This could not be directly implemented. Since, due to the different substitution pattern, conjugation and stabilization of the enamine by the ester, as in WO 2012 / 137982, cannot occur, this was not an obvious approach. For example, a corresponding enamine analogous to that in WO 2012 / 137982 could not be isolated from 4-oxotetrahydrofuran-2-carboxylic acid methyl ester. Under these conditions, the benzylamide of the ester is formed instead. Furthermore, reduction with hydrogen over a catalyst is necessary to obtain the desired cis-selectivity. Reductive amination with ammonia or ammonium salts was also unsuccessful. Explanation of the processes and intermediate products Examples

[0033] The present invention will be explained in more detail with reference to the following examples, without limiting the invention to these. Measurement methods

[0034] The products were characterized using 1< H-NMR spectroscopy, standard HPLC from Agilent and / or GC / MS (Gas Chromatography Mass Spectrometry).

[0035] The NMR spectra were measured using a Bruker AV III 600.

[0036] The GC / MS samples were analyzed using a Shimadzu GCMS-QP-2010-Ultra coupled with an additional flame ionization detector (FID). The samples were first evaporated, and then 1-10 mg of dry sample was reacted with 250 µL of N-methyl-N-trimethylsilyltrifluoroacetamide for silylation. After a reaction time of 1-5 minutes, the samples were diluted with 1 mL of acetonitrile and analyzed. Inventive step 1 Example 1 rac-cis-4-(Benzylamino)tetrahydrofuran-2-carboxylic acid methyl ester hydrochloride

[0037] To a solution of 49.3 g (343 mmol) benzylamine hydrochloride and 250 g methanol in a 600 ml autoclave, 50 g (343 mmol, 1 eq) of 4-oxotetrahydrofuran-2-carboxylic acid methyl ester and 5 g (0.44 mmol) of 5% Pt / C catalyst (66% water-moist) were added. The autoclave was purged three times with 5 bar argon, and then the mixture was stirred under 5 bar hydrogen for 16 h at 20°C and 600 rpm. Afterward, the autoclave was depressurized, the reaction mixture was filtered off via a Büchner funnel, and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to 290 g and treated with 250 g of cyclopentyl methyl ether (CPME). The solution was then concentrated under reduced pressure to 274 g. The resulting suspension was mixed with 50 g of CPME and 15 g of methanol, then stirred for 15 min at 40°C and 1 h at room temperature, and then filtered through a Büchner funnel. The residue was washed with CPME / MeOH and dried under reduced pressure.

[0038] GC / MS (m / z): 205 [M-CH2O], 190, 176, 146, 132, 114, 106, 91, 82, 65.

[0039] 1<H-NMR (DMSO-d6, 600 MHz): 2.1-2.2 (1H, m), 2.63-2.72 (1H, m), 3.69 (3H, s), 3.79-3.9 (1H, m), 3.9-4.05 (2H, m), 4.07-4.21 (2H, m), 4.47-4.55 (1H, t), 7.35-7.5 (3H, m), 7.51-7.61 (2H, m), 9.5-9.7 (2H, br) ppm. Purity (qNMR): 94% Yield: 56.4 g of the title compound (57% of theory) Examples 2-13

[0040] The following experiments were carried out analogously to the experimental stirring used to prepare Example 1. The yield of the target compound in solution was determined by quantitative NMR spectroscopy of the solution. The product was not isolated. Nr. Connection Formula (III) Catalyst [wt.%] solvent Pressure [bar] Temperature [°C] Time [h] cis / trans ratio Yield, solution [%] 2 BnNH 2 10 MeOH 5 20 16 7,1 59 3 BnNH 2 10 2-ProH 5 20 16 7,3 51 4 BnNH 2 10 2-BuOH 5 20 16 5,9 72 5 BnNH 2 3,5 tert-Amyl alcohol 5 22 16 7,8 78 6* BnNH 2 3,0 MeOH 5 22 16 5,4 76 7 BnNH 2 *HCl 10 MeOH 50 20 16 6,6 80 8 BnNH 2 *HCl 10 MeOH 30 35 16 6,6 77 9 BnNH 2 *HCl 10 MeOH / Toluene (70 / 30) 5 20 16 7,3 80 10 BnNH 2 *HCl 5 MeOH / Toluene (70 / 30) 20 60 16 6,6 66 11** BnNH 2 *HCl 10 MeOH / Toluene (70 / 30) 5 20 16 9,8 65 12 BnNH₂ *HCl + BnNH₂ 3 MeOH 30 35 24 5,8 75 13*** BnNH 2 *HCl 3 MeOH 30 35 24 5,0 76 * BnNH₂ dosed over 4 hours; *** 10 wt% zinc chloride added; *** compound (II) Dosed over 4 hours. Example 14 rac-cis-4-(2-methylbenzylamino)tetrahydrofuran-2-carboxylic acid methyl ester hydrochloride

[0041] To a solution of 54.1 g (343 mmol) of 2-methylbenzylamine hydrochloride and 300 ml of methanol in a 600 ml autoclave, 50 g (343 mmol, 1 eq) of 4-oxotetrahydrofuran-2-carboxylic acid methyl ester and 5 g (0.44 mmol) of 5% Pt / C catalyst (66% water-wet) were added. The autoclave was purged three times with 5 bar argon, and then the mixture was stirred under 5 bar hydrogen for 16 h at 20°C and 600 rpm. Subsequently, a further 2.5 g (0.22 mmol) of 5% Pt / C catalyst (66% water-wet) was added, and hydrogenation continued under the same conditions. The autoclave was then depressurized, the reaction mixture was filtered off via a Büchner funnel, and the residue was washed with methanol. The filtrate was concentrated to 125.7 g under reduced pressure.

[0042] GC / MS (m / z): 219 [M-CH2O], 204, 190, 160, 146, 132, 120, 105, 91, 82, 79, 77, 69.

[0043] 1<H-NMR (DMSO-d6, 600 MHz): 2.19-2.28 (1H, m), 2.4 (3H, s), 2.7-2.78 (1H, m), 3.68 (3H, s), 3.9-4.02 (2H, m), 4.03-4.2 (3H, m), 4.47-4.55 (1H, t), 7.22-7.35 (3H, m), 7.55 (1H, d), 9.6-9.8 (2H, br) ppm. Purity (qNMR): 57% Yield: 125.7 g of the title compound (73% of theory) Inventive step 2 Example 15 rac-cis-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride

[0044] To a solution of 16 g (57.9 mmol) of cis-4-(benzylamino)tetrahydrofuran-2-carboxylic acid methyl ester hydrochloride, 56 g of methanol, and 24 g of toluene in a 300 mL autoclave, 80 mg (0.025 mmol) of 5% Pd / C catalyst (33% water-moist) were added. The autoclave was purged three times with 5 bar argon, and then the mixture was stirred under 5 bar hydrogen pressure for 16 h at 65°C and 600 rpm. The autoclave was cooled to room temperature and depressurized. The reaction mixture was filtered through a Büchner funnel, and the filtrate was concentrated under reduced pressure. The solvent mixture was then adjusted to a toluene:MeOH ratio of 90:10. The solution was cooled from 66°C to room temperature with stirring, and the suspension was filtered through a Büchner funnel at room temperature. The residue was washed with 5 ml each of toluene:MeOH=10:1 and toluene and then dried under reduced pressure.

[0045] GC / MS (m / z): 217 [M+TMS], 202, 187, 172, 158, 142, 128, 116, 100, 89, 73, 59, 54.

[0046] 1< H-NMR (DMSO-d6, 600 MHz): 1.95-2.04 (1H, m), 2.59-2.67 (1H, m), 3.70 (3H, s), 3.75-3.85 (2H, m), 3.9-3.97 (1H, m), 4.45-4.52 (1H, t), 8.2-8.5 (3H, br) ppm. Purity (qNMR): 98% Yield: 9.86 g of the title compound (92% of theory) Example 16 rac-cis-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride

[0047] To a solution of 125 g (56.9% purity, 249 mmol) of cis-4-(2-methylbenzylamino)tetrahydrofuran-2-carboxylic acid methyl ester hydrochloride and 250 g of methanol in a 600 mL autoclave, 2 g (0.94 mmol) of 5% Pd / C catalyst were added. The autoclave was purged three times with 5 bar argon, and then the mixture was stirred under 5 bar hydrogen for 16 h at 65°C and 600 rpm. The autoclave was cooled to room temperature and depressurized. The reaction mixture was filtered through a Büchner funnel, the residue was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was recrystallized with 22 g of methanol and 182 g of xylene. The crystal slurry was filtered through a Büchner funnel, washed with xylene, and dried under reduced pressure.

[0048] GC / MS (m / z): 217 [M+TMS], 202, 187, 172, 158, 142, 128, 116, 100, 89, 73, 59, 54.

[0049] 1< H-NMR (DMSO-d6, 600 MHz): 1.95-2.04 (1H, m), 2.59-2.67 (1H, m), 3.70 (3H, s), 3.75-3.85 (2H, m), 3.9-3.97 (1H, m), 4.45-4.52 (1H, t), 8.2-8.5 (3H, br) ppm. Purity (qNMR): 80% Yield: 52.4 g of the title compound (93% of theory)

Claims

1. Process for preparing compounds of the general formula (I) or salts thereof in which R1 is (C1-C6) alkyl or (C3-C6) cycloalkyl, characterized in that in a first step compounds of the general formula (II) in which R1 is as defined above, react with an amine of the general formula (III) or salts thereof in which R2 is H, (C1-C4) alkyl, unsubstituted or substituted phenyl, R3 is H, halogen, (C1-C4) alkyl or (C1-C4) alkoxy, in the presence of H2 and a catalyst in a solvent, selected from R1OH, R1OH / toluene, 2-PrOH, 2-BuOH or t-amyl alcohol, where R1 is as defined above, to form compounds of the general formula (IV) or salts thereof where R1, R2 and R3 are as defined above, and said compounds are then converted in the presence of H2 and a catalyst in a solvent, selected from R1OH, R1OH / toluene, 2-PrOH, 2-BuOH or t-amyl alcohol, where R1 is as defined above, into compounds of the general formula (I) or salts thereof.

2. Process according to Claim 1, characterized in that the definitions of the radicals for the compounds of the general formulae (I), (II), (III) and (IV) or salts thereof are as follows: R1 is (C1-C6) alkyl, R2 is H, phenyl, methyl, R3 is H, F in para position of the phenyl ring, methyl-O- in para position of the phenyl ring, methyl in ortho position of the phenyl ring.

3. Process according to Claim 1, characterized in that the definitions of the radicals for the compounds of the general formulae (I), (II), (III) and (IV) or salts thereof are as follows: R1 is CH3, R2 is H, R3 is H or methyl in ortho position of the phenyl ring.

4. Process according to any of Claims 1 to 3, characterized in that the reaction of step 1 is conducted at 20°C to 40°C.

5. Process according to any of Claims 1 to 4, characterized in that the reaction of step 2 is conducted at 40°C to 80°C.

6. Process according to any of Claims 1 to 5, characterized in that the compounds of the general formulae (III), (IV) and (I) are present as hydrochloride salt.

7. Process according to any of Claims 1 to 6, characterized in that the catalyst in step 1 is Pt / C.

8. Process according to any of Claims 1 to 7, characterized in that the catalyst in step 2 is Pd / C.